1. Field of the Invention
The present invention relates to the treatment in an ophthalmologic field, more particularly, to ophthalmic pharmaceutical compositions for treating and/or preventing the ophthalmologic clinical symptoms and signs in Sjxc3x6gren syndrome.
2. Description of the Prior Art
Sjxc3x6gren syndrome is one of the frequently diagnosed diseases and is often found particularly in older ages. It is estimated that patients with such a syndrome will increase in number more and more as coming into the aging society. As characteristic features, Sjxc3x6gren syndrome is accompanied by the invasion of lymphocytes into the lacrimal gland and the salivary gland, and the disruption of adenocytes, and is characterized mainly by dry eye and dry mouth. Sjxc3x6gren syndrome is a cryptogenic disease or the like and is highly speculated as an autoimmune disease, and the criterion has been already established. The ophthalmologic clinical symptoms of Sjxc3x6gren syndrome are, for example, foreign body sensation, burning, and itching. Treatments for Sjxc3x6gren syndrome now used predominantly are symptomatic therapies such as the application of artificial tears and the wear of goggles and glasses for preventing dry eye. When the symptoms of patients with these treatments are not improved, they are then treated mainly with other symptomatic therapies such as surgeries and the administration of steroids and immunosuppressants in combination, which may restrict patient""s normal social life because these therapies would require hospitalization, doctor""s advice, or therapeutic devices. Conventional ophthalmic solutions used generally in the ophthalmologic field are easily portable and readily usable when in use, and therefore ophthalmic solutions, containing sodium hyaluronate for treating the ophthalmologic clinical symptoms and signs in Sjxc3x6gren syndrome, have been commercialized recently, however, any satisfactory ophthalmic pharmaceutical composition for treating and/or preventing the syndrome has not been provided yet.
The object of the present invention is to provide an ophthalmic pharmaceutical composition with a satisfactory therapeutic and/or prophylactic effect on the ophthalmologic clinical symptoms and signs in Sjxc3x6gren syndrome, as well as advantageous usefulness and safety; and more particularly to an ophthalmic solution, ointment, and eyewash.
In view of the foregoing, the present inventors screened substances which have a satisfactory therapeutic and/or prophylactic effect on the ophthalmologic clinical symptoms and signs in Sjxc3x6gren syndrome and have safety even when used for a relatively-long period of time. As a result, the present inventors unexpectedly found that trehalose, which is widely used in food products and cosmetics, exerts an outstanding therapeutic and/or prophylactic effect on the clinical symptoms and signs in Sjxc3x6gren syndrome without any side effect even after a relatively-long time administration; the present invention solves the above object by the ophthalmic pharmaceutical composition comprising trehalose as an effective ingredient.
Trehalose, a disaccharide composed of two glucose molecules linked together at their reducing residues, has 3-types of optical isomers of xcex1,xcex1-trehalose, xcex1,xcex2-trehalose, and xcex2,xcex2-trehalose, which are hereinafter called xe2x80x9ctrehalosexe2x80x9d, if specified otherwise. In the natural world, trehalose is widely distributed in bacterial, plant, and animal worlds. In the field of food products, trehalose has been being greatly increased in demand because of its remarkable characteristic features such as relatively-low sweetness, prevention of retrogradation of starches, and prevention of denaturation of proteins during freezing/drying. In the field of cosmetics, the use of trehalose has been wide-spreading because of its satisfactory moisture-retaining ability, and the safety of oral administration and dermatological application of trehalose has been already confirmed. However, as for the physiological functions of trehalose, there have only been known the improvement of osteoporosis and the regulation of metabolism of serum fatty acids, while in the field of ophthalmology, only reported is the action of trehalose to protect cells in the corneal endothelium and the corneal epithelium susceptible to damage induced by ophthalmic surgeries as disclosed in Japanese Patent Kokai No. 235,233/97.
As described above, trehalose per se is a well-known compound, however, it was firstly found in the present invention that trehalose exerts a satisfactory therapeutic and/or prophylactic effect on the ophthalmologic clinical symptoms and signs in Sjxc3x6gren syndrome.
The present invention relates to an ophthalmic pharmaceutical composition for treating and/or preventing the ophthalmologic clinical symptoms and signs in Sjxc3x6gren syndrome, which comprises trehalose as an effective ingredient. As described above, there exist three types of optical isomers of trehalose, i.e., xcex1,xcex1-trehalose, xcex1,xcex2-trehalose, and xcex2,xcex2-trehalose, which all exert an effective therapeutic and/or prophylactic effect on the ophthalmologic clinical symptoms and signs in Sjxc3x6gren syndrome, and therefore one or more of these optical isomers can be arbitrarily used in combination in the present invention. In the ophthalmic pharmaceutical compositions of the present invention, each of the optical isomers of trehalose can be used alone or two or more of them can be used in combination independently of their combination use and preparation methods, as long as they contain an effective amount of trehalose.
Any trehalose can be used in the present invention independently of its preparation methods and origin, as long as it does not spoil the present object. Examples of the methods for producing xcex1,xcex1-trehalose include the enzymatic methods as disclosed in Japanese Patent Kokai Nos. 143,876/95, 213,283/95, 322,883/95, 298,880/95, 66,187/96, 66,188/96, 336,388/96, and 84,586/96, where non-reducing saccharide-forming enzymes and trehalose-releasing enzymes are allowed to act on starch hydrolysates to form xcex1,xcex1-trehalose. The trehalose thus obtained can be advantageously used because of its economical merit and lesser possibility of the contamination of harmful impurities as compared with those prepared by synthetic methods. Examples of commercialized trehalose produced by the above enzymatic methods are xe2x80x9cTREHA(copyright)xe2x80x9d, a trehalose having a trehalose content of 98%, on a dry solid basis (d.s.b.), commercialized by Hayashibara Shoji, Inc., Okayama, Japan; and a reagent grade trehalose having a trehalose content of 99% or higher, d.s.b., commercialized by Hayashibara Biochemical Laboratories, Inc., Okayama, Japan. The trehalose usable in the present invention should not be restricted to the ones above, however, the above trehalose products can be advantageously used.
The xcex1,xcex2-trehalose usable in the present invention can be produced, for example, by the method as disclosed in Japanese Patent Kokai No. 179,490/92 where an enzyme is allowed to act on a mixture of starch hydrolysate and lactose, while the xcex2,xcex2-trehalose usable in the present invention can be chemically synthesized easily. The trehalose used in the present invention should not necessarily be in an isolated form or may be in a mixture form of trehalose and other saccharides that are formed during the production of trehalose, as long as they do not spoil the therapeutic and/or prophylactic effect by trehalose on the ophthalmologic clinical symptoms and signs in Sjxc3x6gren syndrome. Of course, impurities such as pyrogens should preferably be removed by using activated charcoal, ion-exchange chromatography, gel filtration chromatography, and membrane filtration because ophthalmic solutions are directly applied to the ocular-mucous membranes.
When administered to patients with the ophthalmologic clinical symptoms of Sjxc3x6gren syndrome such as foreign body sensation, burning, and itching, the ophthalmic pharmaceutical composition of the present invention improves the above symptoms and, when administered to patients with inconsistent onset and restoration of the symptoms during a symptomless period, it can prevent the occurring of such symptoms. The ophthalmic pharmaceutical composition of the present invention can be used in the form of an eyewash, ophthalmic solution, or ophthalmic ointment.
The ophthalmic pharmaceutical composition of the present invention can be prepared using commonly used pharmaceutically-acceptable carriers in such a manner of mixing them with an effective amount of trehalose to suit the desired formulation. The carriers used for ophthalmic solutions and eyewashes include any one of those which are commonly used therefor, usually, purified water. The ophthalmic pharmaceutical composition of the present invention can be previously prepared into a solution form or processed into a solid preparation using lyophilization method, etc., to be used after dissolving when in use in such a manner of dissolving the solid preparation in solvents such as purified water and physiological saline. Examples of such a solid preparation include tablets, granules, and powders. To prepare the ophthalmic pharmaceutical composition in the form of an ointment, petrolatum, and propeto for ophthalmic use can be used. These ophthalmic pharmaceutical compositions can be prepared in accordance with conventional methods and should preferably be sterilized before use by conventional methods using membrane filters, autoclaves, etc.
The content of trehalose in the ophthalmic pharmaceutical composition of the present invention is usually set to give a final concentration of at least 0.01% by weight or in the range of about 0.01 to about 30% by weight, preferably, 0.5 to 20% by weight, and most preferably, 2 to 10% by weight from a viewpoint of therapeutic and/or prophylactic effect on both the ocular-mucous membranes and the ophthalmologic clinical symptoms and signs in Sjxc3x6gren syndrome. The aforesaid concentration of trehalose means the concentration expressed by a percent by weight per volume (w/v) as for liquid eyewashes and ophthalmic solutions, or the concentration expressed by a percent by weight per weight (w/w) as for solid ophthalmic ointments. Since the ophthalmic pharmaceutical composition of the present invention directly contacts with the ocular-mucous membranes, the composition should preferably be set to pHs around neutral pHs, most preferably, pHs of 6.5-7.5 with respect to safety; and should preferably be set to osmotic pressures of about 0.5-4.0, more preferably, 1.0-1.5. The pH and the osmotic pressure of the ophthalmic pharmaceutical composition of the present invention can be controlled by conventional methods.
Among saccharides, trehalose quite stably retains its properties, substantially does not cause the amino carbonyl reaction even when coexisted with amino-containing vitamins and peptides, or even stabilizes them. Therefore, the ophthalmic pharmaceutical composition of the present invention can be prepared by appropriately combining with one or more ingredients such as saccharides other than trehalose, electrolytes, amino acids, vitamins, lipids, pharmaceutical additives, and pharmaceuticals.
Concrete examples of the ingredients other than trehalose used in the ophthalmic pharmaceutical composition of the present invention are saccharides such as glucose and maltose; sugar alcohols such as mannitol and sorbitol; electrolytes such as sodium chloride, sodium hydrogenphosphate, potassium chloride, magnesium sulfate, and calcium chloride; amino acids such as glycine and alanine; vitamins and derivatives thereof such as thiamine hydrochloride, sodium riboflavin phosphate, pyridoxine hydrochloride, nicotinamide, folic acid, biotin, vitamin A, L-ascorbic acid, and xcex1-glycosyl-L-ascorbic acid, which all can be used in an appropriate combination. Particularly, in the case of the ophthalmic pharmaceutical composition of the present invention is in the form of an ophthalmic solution, the combination use of trehalose as an effective ingredient and one or more other saccharides selected from monosaccharides such as glucose and fructose, disaccharides such as maltose, and oligosaccharides higher than maltotriose tends to more stably exert a satisfactory therapeutic and/or prophylactic effect on the ophthalmologic clinical symptoms and signs in Sjxc3x6gren syndrome. In this case, the ratio of a saccharide(s) other than trehalose is 0.0001-10 times, preferably, 0.001-5 times, and more preferably, 0.001-2 times of trehalose in an anhydrous form. In addition, one or more of the following additives used in conventional ophthalmic preparations can be used in the ophthalmic pharmaceutical composition of the present invention as long as they do not spoil the present object; preservatives such as methyl p-hydroxybenzoate, sodium dehydroacetate, and benzalkonium chloride; buffers such as borax (sodium borate), boric acid, and sodium hydrogencarbonate; viscosity-imparting agents such as methyl cellulose, carboxy methyl cellulose, chondroitin sulfate, polyvinyl alcohol, and pullulan; solubilizers such as polysorbate 80; and stabilizers such as sodium edetate, and sodium hydrogensulfite. In the ophthalmic pharmaceutical composition of the present invention, the above preservatives such as methyl p-hydroxybenzoate, sodium dehydroacetate, and benzalkonium chloride may not preferably be used because they may induce allergy in some patients.
When the ophthalmic pharmaceutical composition of the present invention is in the form of an ophthalmic ointment, conventional carriers used for ophthalmic ointments can be used; for example, white petrolatum and plastibase for ophthalmic use. The additives used in such an ophthalmic ointment include liquid paraffin. If necessary, the ophthalmic pharmaceutical composition of the present invention can be used in an appropriate combination with steroid hormones such as methylprednisolone; anti-inflammatories such as tetracycline; antiseptics such as penicillin G; immunosuppressants such as cyclosporin; and pharmaceuticals such as immunomodulators, analgesics, autosera, and hyaluronic acid.
The signature-dosage of the ophthalmic pharmaceutical composition of the present invention can be appropriately controlled depending on the symptoms and signs of patients. When used as an ophthalmic solution, the ophthalmic pharmaceutical composition of the present invention is administered to patients at a dose of one to four drops (about 0.025 to about 0.1 ml) per shot one to ten times a day. When used as an eyewash, the ophthalmic pharmaceutical composition of the present invention is usually used in such a manner of pouring an about five milliliters of the eyewash in an exclusive container that can be closely applicable to the face-line around the patient""s eyes, applying the container to the face-line, allowing the patients to lean back to face up, and allowing the patients to blink several times to allow to contact their eyes with the composition at a dose of one to six times a day; or used in such a manner of washing their eyes using a washing bottle at a dose of one to five times a day using about one to about five milliliters of the eyewash per shot.
The following examples describe the present invention but do not restrict the present invention: